Macrophages and macrophage elastase are thought to be integral components in the pathogenesis of emphysema. The increased numbers of more highly activated macrophages, capable of increased elastase secretion, which are found in association with chronic inflammation and in the lungs of cigarette smokers, make them likely candidates. The overall objective of this study is to further investigate the role of the macrophage and macrophage elastase in the pathogenesis of emphysema. To accomplish this goal we have proposed three major projects. The first objective is to purify macrophage elastase and to characterize it biochemically and immunologically. Isolation of this enzyme will permit a closer scrutiny of its role in emphysema, principally by permitting the study of the interaction of macrophage elastase with a variety of natural and synthetic substrates and inhibitors. The second objective is to determine if alveolar macrophages secrete alpha-2-macroglobulin, and to study its interaction with elastase. The third objective is to investigate the effect of cigarette smoke on the secretion of elastase by cultured macrophages. This will be performed by treating cultured macrophages with aqueous cigarette smoke extracts for various time intervals, and examining the effects of this treatment on elastase secretion and cell viability. Thus, the long range goal of this reseach project is to examine the induction macrophage elastase by cigarette smoke, to purify and characterize the enzyme, and to study its interaction with naturally-occurring inhibitors principally with alpha-2-macroglobulin.